RET is one of the receptor tyrosine kinases and is a cell surface molecule that transduces signals for cell growth and differentiation.
RET mutation is known to be involved in diseases such as multiple endocrine neoplasia, type IIA, multiple endocrine neoplasia, type IIB, familial medullary thyroid carcinoma, sporadic medullary thyroid carcinoma, papillary thyroid carcinoma and Hirschsprung disease. (Oncogene, 19, 5590-5597, 2000; Cancer Research, 15, 7284-7290, 2002.) RET kinase inhibiting substance has been suggested as a potentially effective therapeutic agent for said diseases. (Oncogene, 19, 5590-5597, 2000; Cancer Research, 15, 7284-7290, 2002.)
Mutation of one of five cysteine residues at codons 609, 611, 618, 620 and 634 of RET is found in 93-98% of the patients with multiple endocrine neoplasia, type IIA, where mutation at RET codon 634 is found most frequently. (Cancer Research, 66, 1177-1180, 2006; Journal of Clinical Endocrinology and Metabolism, 88, 5438-5443, 2003.)
On the other hand, mutation M918T (mutation from methionine to tyrosine at codon 918) of RET is found in 95% of the patients with multiple endocrine neoplasia, type IIB. (Journal of Clinical Endocrinology and Metabolism, 88, 5438-5443, 2003.)
Mutation at one of RET codons 609, 611, 618, 620, 634, 768, 790, 791, 804 and 891 is found in many of the patients with familial medullary thyroid carcinoma, (Journal of Clinical Endocrinology and Metabolism, 88, 5438-5443, 2003.)
All of these point mutations are known to cause constant ligand-independent RET activation. (Cancer Research, 66, 1177-1180, 2006; Journal of Clinical Endocrinology and Metabolism, 88, 5438-5443, 2003.)
A syndrome of multiple endocrine neoplasia, type IIA is characterized by medullary thyroid carcinoma, pheochromocytoma and parathyroid hyperplasia whereas a syndrome of multiple endocrine neoplasia, type IIB is associated with medullary thyroid carcinoma, pheochromocytoma and mucosal neuromas of the gastrointestinal tract. Chief symptom of syndrome of familial medullary thyroid carcinoma is medullary thyroid carcinoma. (Journal of Clinical Endocrinology and Metabolism, 89, 4142-4145, 2004.)
Point mutation of RET somatic cells is found in about 40% of the patients with sporadic medullary thyroid carcinoma while mutations are mostly found at codon 918. (Journal of Clinical Endocrinology and Metabolism, 89, 5823-5827, 2004.)
Moreover, a fusion gene of RET gene and other gene, namely, rearrangement of RET gene, is found in papillary thyroid carcinoma due to chromosomal inversions or chromosomal translocation. The fusion protein generated via RET gene rearrangement is known to lead to ligand-independent dimerization and constant RET activation. (Endocrinology, 145, 5448-5451, 2004.)
Hirschsprung disease is characterized by persistent constipation and intestinal dilatation in newborns caused by abnormal colonic nerve plexus. One of the causes of Hirschsprung disease is known to be RET mutation, (Proceedings of the National Academy of Sciences of the United States of America, 102, 8949-8954, 2005.)
RET mutation has been reported to cause scaffold-independent proliferation and tumorigenesis in NIH3T3 cells. (Cancer Research, 15, 7284-7290, 2002.)
RET kinase inhibiting substance ZD6474 has been reported to suppress scaffold-independent proliferation in NIH3T3 cells transformed with mutant RET and inhibited tumor formation after infusion of said cells into nude mice. (Cancer Research, 15, 7284-7290, 2002.)
RET kinase inhibiting substance BAY 43-9006 has been reported to reduce the size of tumor in a model for subcutaneous transplantation of human medullary thyroid carcinoma cell line (TT). (Journal of the National Cancer Institute, 98, 326-334, 2006.)
Hence, RET kinase inhibiting substances are suggested to induce cell growth inhibition for cells expressing mutant RET and show antitumor effect against these tumor cells. RET kinase inhibiting substances also appear to be effective against diseases caused by RET mutation.
Thus, RET kinase inhibiting substances are expected to be effective against multiple endocrine neoplasia, type IIA, multiple endocrine neoplasia, type IIB, familial medullary thyroid carcinoma, papillary thyroid carcinoma, sporadic medullary thyroid carcinoma, Hirschsprung disease, pheochromocytoma, parathyroid hyperplasia, mucosal neuromas of the gastrointestinal tract and thyroid carcinoma.
4-(3-chloro-4-(cyclopropyl aminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide and analogs thereof are known as angiogenesis inhibiting substances. (International Publication No. 02/32872, pamphlet; International Publication No. 2004/080462, pamphlet; International Publication No. 2005/063713, pamphlet.) However, none has reported as to what 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide and analogs thereof have RET kinase-inhibiting activity.